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    1,2,4-Triazole-Acetamide Conjugates as hEGFR Inhibitors: Synthesis, Anticancer Evaluation, and In Silico Studies
    (Wiley-V C H Verlag Gmbh, 2026) Bulbul, Bahadir; Kulabas, Necla; Gurboga, Merve; Ozakpinar, Ozlem Bingol; Cakmak, Ummuhan; Tuncay, Fulya Oz; Kucukguzel, Ilkay
    A series of novel 1,2,4-triazole-acetamide derivatives was synthesized and evaluated for anticancer and hEGFR inhibitory activity. The compounds were obtained via multistep synthesis and characterized by spectroscopic methods. Cytotoxicity was tested against PC-3, MCF-7, A549, and K562 cell lines. Compounds 18, 19, and especially 24 showed notable antiproliferative effects, with compound 24 exhibiting higher selectivity and potency than gefitinib. It also induced apoptosis and inhibited migration in A549 and PC-3 cells, while selectively promoting invasion in PC-3, suggesting EMT-related behavior. In vitro kinase assays revealed compound 20 as the most potent hEGFR inhibitor (IC50 = 43.8 +/- 1.3 nM). Molecular docking and 200 ns molecular dynamics simulations confirmed its stable interaction with EGFR, particularly involving Cys797. These findings highlight compounds 20 and 24 as promising candidates for further development as EGFR-targeted anticancer agents.
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    CADD-guided design of novel triclosan-hydrazone hybrids with antibacterial and antimycobacterial activity as InhA inhibitors
    (Elsevier, 2026) Birgul, Kaan; Bulbul, Bahadir; Birgul, Serap Ipek Dingis; Sahin, Goknil Pelin Coskun; Curcio, Antonio; Vatansever, Cansu; Brancale, Andrea
    The development of new antitubercular agents targeting essential enzymes of Mycobacterium tuberculosis remains a critical priority due to the global rise of drug-resistant tuberculosis. In this study, a series of triclosan-inspired hydrazone hybrids was designed to explore whether incorporation of a hydrazone linker into the diphenyl ether scaffold could generate compounds with antibacterial and antimycobacterial activity while maintaining potential interaction with the enoyl-ACP reductase InhA. Sixteen derivatives were synthesized through a three-step synthetic route starting from triclosan and were structurally characterized by 1H NMR, 13C NMR, HRMS, FT-IR, and HPLC analysis. Molecular docking and molecular dynamics simulations were performed to investigate the potential interaction of the compounds with both holo and apo forms of InhA. Among the series, compounds 3g and 3j displayed docking poses most comparable to triclosan and showed stable interaction patterns during molecular dynamics simulations. Microbiological evaluation revealed selective antibacterial activity against Gram-positive bacteria, while Gram-negative strains remained largely insensitive. The most active compound against Staphylococcus epidermidis ATCC 12228 was 3i (MIC = 1 mu g/mL). In antimycobacterial assays against M. tuberculosis H37Rv, compounds 3f and 3m demonstrated the most potent activity (MIC = 6.25 mu g/mL). Enzymatic assays showed moderate inhibition of InhA for compounds 3g and 3j (<= 56% inhibition at 50 mu M), suggesting that these derivatives can interact with the enzyme, although InhA inhibition alone may not fully account for the observed whole-cell activity. Overall, the results indicate that triclosan-hydrazone hybrids represent a synthetically accessible scaffold capable of producing compounds with measurable antibacterial and antimycobacterial activity. While the removal of the phenolic hydroxyl group reduced direct InhA inhibition compared with triclosan, the present study highlights the potential of this scaffold for further optimization toward improved enzyme binding, physicochemical properties, and antimycobacterial potency.